1. Field of the Invention
This invention relates to a method for increasing the growth rates of human patients having partial growth hormone insensitivity syndrome.
2. Description of Background and Related Art
Most children who are evaluated for short stature do not have growth hormone deficiency as defined by the growth hormone (GH) response to provocative stimuli. Once other causes of short stature have been excluded, the patient is usually classified as having familial short stature, constitutional delay of growth, or "idiopathic" short stature (ISS). Despite not being classically GH deficient, most children with ISS respond to treatment with GH, although not as well. Since there are so many factors that contribute to normal growth and development, it is likely that this group of patients is heterogeneous with regard to their etiology of short stature.
Many investigators have searched for disturbances in spontaneous GH secretion in this set of patients. One hypothesis suggests that some of these patients have inadequate secretion of endogenous GH under physiologic conditions, but are able to demonstrate a rise in GH in response to pharmacologic stimuli, as in traditional GH stimulation tests. This disorder has been termed "GH neurosecretory dysfunction," and the diagnosis rests on the demonstration of an abnormal GH pattern on prolonged serum sampling. Numerous investigators have reported results of such studies, and have found this abnormality to be only occasionally present. Other investigators have postulated that these patients have "bioinactive GH;" however, this has not yet been demonstrated.
When the GH receptor was cloned, it was shown that the major GH binding activity in blood was due to a protein which derives from the same gene as the GH receptor and corresponds to the extracellular domain of the full-length GH receptor. Most patients with growth hormone insensitivity (or Laron) syndrome (GHIS) lack growth hormone receptor binding activity and have absent or very low GH-binding protein (GHBP) activity in blood. Such patients have a mean height standard deviation score of about -5 to -6, are resistant to GH treatment, and have increased serum concentrations of GH and low serum concentrations of insulin-like growth factor (IGF-I). They respond to treatment with IGF-I. In patients with defects in the extracellular domain of the GH receptor, the lack of functional GHBP in the circulation can serve as a marker for the GH insensitivity.
There is a subclass of patients with ISS having low GHBP in their blood who have a mean height standard deviation score intermediate between patients with complete GHIS (Laron syndrome) and normal children, and who respond somewhat, but not completely, to GH treatment. This class of patients can be characterized as having partial GHIS.
It is an object of the present invention to identify a subset of patients with ISS who exhibit partial GHIS and do not have complete GHIS or Laron syndrome.
It is another object to treat this identified subset of patients so that they attain ultimate height consistent with their genetic potential as determined by the mid-parental target height.
These and other objects will be apparent to those of ordinary skill in the art.